Forty-five percent of children with neuroblastoma have high-risk disease, which is usually metastatic when diagnosed. Despite the improvement in outcome that has been achieved with intensive, myeloablative therapy followed by 13-cisretinoic acid, the long-term survival for these patients remains poor at approximately 40 percent. Poor responses or recurrences in primary and metastatic sites, particularly bone and bone marrow, are the causes of failure. Hypothesis: Further improvement in survival for patients with high-risk neuroblastoma will require new therapeutic strategies that overcome resistance to chemotherapy, irradiation, and/or retinoic acid and that do not have overlapping toxicities with current "standard" therapies long-term goal. The goal of this Program Project is to improve survival for children with high-risk neuroblastoma by integrating biology and developmental therapeutics research with phase I and II clinical trials specific aims. Project 1: The tumor microenvironment is investigated with emphasis on angiogenesis (tumor cell and bone marrow derived endothelial, inflammatory, and pericyte interactions) and bone metastasis (tumor, bone marrow mesenchymal, and osteoclast interactions), Project 2. Immunotherapy strategies focus on natural killer (NK) cells. Studies aim to maximize NK infiltration and anti-tumor activity in various tumor microenvironments by increasing production of NK-attracting chemokines from tumor and non-tumor cells and to increase neuroblastoma cell susceptibility to direct and antibody dependent NK cytotoxicity. Project 3: The cytotoxic retinoid, fenretinide, and agents that synergize with it to increase ceramide induction of tumor cell death are investigated. Mechanisms of ceramide modulation by these agents and delivery of drugs to the tumor microenvironment are studied to maximize this new therapy: Project 4: New strategies developed in our laboratories are tested in phase I trials by the New Approaches to Neuroblastoma Therapy (NANT) consortium (www.nant.org), which includes 14 pediatric oncology institutions across the US. High-dose myeloablative therapy, chemotherapy, and biologic therapy protocols are active. Laboratory components include pre-clinical drug testing to identify potentially active agents and pharmacokinetics and pharmacodynamics for drug and immunotherapy trials. Research Design. Projects 1-3 perform biologic and developmental therapeutic studies using molecular and cell biology techniques, neuroblastoma tumors from patients, a large panel of neuroblastoma cell lines, NK cells, and neuroblastoma cell lines growing as primary and metastatic tumors in immunodeficient mice. Project 4 performs clinical trials. Core components provide research support, histopathology, immunohistochemistry, electron microscopy, digital image scanning microscopy, flow cytometry, small animal models and in vivo imaging, and biostatistics conclusion. We anticipate that this Program Project will discover therapies that will significantly improve the outcome of patients with high-risk neuroblastoma.